The long term goals of this proposal are to define the role of the HBx gene of human hepatitis B virus (HBV) in inducing hepatocellular carcinoma in transgenic mice, and to apply this transgenic mouse model toward the understanding of the molecular mechanisms for multistage carcinogenesis in humans. This project has four specific bu interrelated aims: [1] to define the role of the HBV X gene (designated HBx gene) in inducing pathogenesis by introducing this gene under its own transcriptional control signals into the germline of mice; [2] to accelerate the disease phenotype that may be induced by the HBx gene by placing it under the control region of the mouse albumin gene and using this chimeric construct to derive transgenic mice which will express high levels of the HBx gene product; [3] to determine the importance of co-factors which may play a role in either inducing or enhancing the manifestation of liver disease in the transgenic mice; [4] to identify the cellular genes and cellular gene products which are specifically activated in the liver of the HBx transgenic mice and to delineate their roles in the process of pathogenesis. It is anticipated that the availability of such transgenic animals would not only facilitate our understanding of HBV-induced disorders, bu may also help elucidate the molecular mechanisms of carcinogenesis.